Acute wounding alters the beta2-adrenergic signaling and catecholamine synthetic pathways in keratinocytes

Raja K Sivamani, Biao Shi, Elizabeth Griffiths, Shirley M. Vu, Hadar A. Lev-Tov, Sara Dahle, Marianne Chigbrow, Thi Dinh La, Chelcy Mashburn, Thomas R. Peavy, Roslyn Rivkah Isseroff

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12 Scopus citations

Abstract

Keratinocyte migration is critical for wound re-epithelialization. Previous studies showed that epinephrine activates the beta2-adrenergic receptor (B2AR), impairing keratinocyte migration. Here, we investigated the keratinocyte catecholamine synthetic pathway in response to acute trauma. Cultured keratinocytes were scratch wounded and expression levels of the B2AR and catecholamine synthetic enzymes tyrosine hydroxylase and phenylethanolamine-N- methyltransferase were assayed. The binding affinity of the B2AR was measured. Wounding downregulated B2AR, tyrosine hydroxylase, and phenylethanolamine-N- methyltransferase expression, but pre-exposure to timolol, a beta-adrenergic receptor antagonist, delayed this effect. In wounded keratinocytes, B2AR-binding affinity remained depressed even after its expression returned to prewounding levels. Keratinocyte-derived norepinephrine increased after wounding. Norepinephrine impaired keratinocyte migration; this effect was abrogated with B2AR-selective antagonist ICI-118,551 but not with B1AR-selective antagonist bisoprolol. Finally, for clinical relevance, we determined that norepinephrine was present in freshly wounded skin, thus providing a potential mechanism for impaired healing by local B2AR activation in wound-edge keratinocytes. Taken together, the data show that keratinocytes modulate catecholamine synthetic enzymes and release norepinephrine after scratch wounding. Norepinephrine appears to be a stress-related mediator that impairs keratinocyte migration through activation of the B2AR. Future therapeutic strategies evaluating modulation of norepinephrine-related effects in the wound are warranted.

Original languageEnglish (US)
Pages (from-to)2258-2266
Number of pages9
JournalJournal of Investigative Dermatology
Volume134
Issue number8
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Sivamani, R. K., Shi, B., Griffiths, E., Vu, S. M., Lev-Tov, H. A., Dahle, S., Chigbrow, M., La, T. D., Mashburn, C., Peavy, T. R., & Isseroff, R. R. (2014). Acute wounding alters the beta2-adrenergic signaling and catecholamine synthetic pathways in keratinocytes. Journal of Investigative Dermatology, 134(8), 2258-2266. https://doi.org/10.1038/jid.2014.137